Tobacco addiction is the single largest cause of cancer and heart disease resulting in 6 million deaths a year world-wide. Vaccines that induce anti-nicotine antibodies and prevent nicotine from crossing the blood brain barrier are an important strategy for smoking cessation, although the concept is not yet proven in humans. Nicotine is non-immunogenic due to its small size and must be conjugated to a larger carrier protein. Thus, the challenge of inducing functional nicotine antibodies requires better methods for presenting nicotine antigens to the immune system. To accomplish this, we have invented a synthetic TriCoil carrier with a high density of nicotine haptens, which is a key determinant of immunogenicity, and a series of CD4 T cell epitopes for regulating B cell help. Proof-of-concept experiments demonstrated that the formulation of this vaccine with the clinical- stage adjuvant GLA-SE, induced a high affinity antibody response in mice that was 10-fold more effective than a conventional nicotine vaccine. We hypothesize that a TriCoil-based vaccine adjuvanted with GLA-SE will activate a larger repertoire of B and T cells in smokers and significantly increase functional anti-nicotine Ab concentrations. To advance this project to the clinic we will complete 2 go/no-go decision points. First, we will down-select a trivalent vaccine in mice with optimized B- and T cell epitopes, and then during year 2, test for efficacy using a gold standard behavioral model in rats. Achievement of this first goal will prompt a study in non-human primates that will establish vaccine superiority relative to a NIC7 mimetic vaccine, which is currently being tested in the clinic. Reaching this second goal during year 3 will trigger initiatin of cGMP manufacturing, GLP-tox safety testing, and submission of an IND during year 5. Successful completion of this project will result in a promising new vaccine for smoking cessation that has several distinct advantages including a structurally- defined hapten carrier, a more potent adjuvant, and a superior manufacturing process for scale-up and commercialization.